Funding for the work described herein was provided by the federal government, which may have certain rights in the invention.
1. Technical Field
The invention relates to methods and materials involved in the treatment of inflammatory disease such as rheumatoid arthritis. In addition, the invention relates to reagents that reduce inflammation as well as animal models for identifying such reagents.
2. Background Information
Rheumatoid arthritis (RA) is a systemic inflammatory disease that preferentially affects the synovial membrane and leads to irreversible damage of cartilage and bone. CD4+ T cells are the dominant cell type in the inflammatory infiltrates that together with the genetic association to MHC class II molecules has been taken as evidence for a central role of T cells in the pathogenesis of the disease (Harris ED Jr, W. B. Saunders (1997)). Tissue infiltrating CD4+ T cells display multiple properties suggestive for local antigen recognition, such as expression of IL-2 receptors and clonal proliferation in the joint (Goronzy J J and Weyand C M, Rheum. Dis. Clin. North Am. 21:655-675 (1995)). Further support for in situ T cell activation has come from the structural organization of T and B cells in the inflamed synovia. In fact, T and B cells have a tendency to form aggregates that morphologically and functionally resemble germinal centers (Kurosaka M and Ziff M, J. Exp. Med 158:1191-1210 (1983) and Schroder A E et al., Pro. NatL. Acad. Sci. U.S.A. 93:221-225 (1996)). Studies on T cell derived cytokines, however, have uniformly demonstrated that T cell products are particularly scarce in rheumatoid synovitis (Firestein G S and Zvaifler N J, Arthritis Rheum. 33:768-773 (1990) and Feldman M et al., Cell 85:307-310 (1996)). The paucity of IL-2- and interferon-xcex3(IFN-xcex3)- producing T cells in the synovial lesions has remained an enigma.
Interleukin-16 (IL-16), originally described as a lymphocyte chemoattractant factor, is a natural ligand of the CD4 molecule (Center D M and W Cruikshank, J. Immunol. 128:-2563-2568 (1982); Cruikshank W W et al., J. Immunol. 146:2929-2934 (1991); Cruikshank W W et al., Proc. Natl. Acad. Sci. U.S.A. 91:5109-5113 (1994); and Ryan T C et al., J. Biol. Chem. 270:17081-17086 (1995)). In fact, IL-16 is a pro-inflammatory cytokine that interacts with CD4 molecules and induces chemotaxis as well as IL-2 receptor and HLA-DR expression (Center D M et al., Int. J. Biochem. Cell Biol. 29:1231-1234 (1997)). Further, IL-16 is synthesized as a precursor protein, pro-IL-16, with CD8+, but not CD4+, T cells having the ability to secrete the bioactive form.
The invention provides methods and materials for treating inflammatory diseases. Specifically, the invention provides methods and materials that reduce expression of an inflammatory cytokine such as IFN-xcex3, IL-1xcex2, and TNF-xcex1 within inflamed tissue. For example, IL-16 polypeptide, IL-16-encoding nucleic acid, and/or an IL-16-mimicking molecule can be administered to a host such that production of an inflammatory cytokine is reduced. Alternatively, cells such as synovial tissue-derived CD8+ T cells can be administered to a host containing inflamed tissue such that production of an inflammatory cytokine is reduced. It is noted that the IL-16 polypeptide, IL-16-encoding nucleic acid, IL-16-mimicking molecule, and/or cells can be administered with an immunosuppressive cytokine polypeptide, immunosuppressive cytokine-encoding nucleic acid, immunosuppressive cytokine-mimicking molecule, and/or cells expressing an immunosuppressive cytokine. Examples of immunosuppressive cytokines include, without limitation, TGF-xcex21, IL-4, and IL-10. The invention also provides methods and materials for identifying reagents that can be used to treat inflammatory diseases. Specifically, the invention provides non-human animals containing human synovial tissue as well as methods for using such non-human animals to determine the influence of various test reagents on the inflamed state of human synovial tissue.
One aspect of the invention features a method for treating an inflammatory disease (e.g., rheumatoid arthritis). The method includes identifying a host having inflamed tissue, and administering a pharmaceutically effective amount of an IL-16 polypeptide or an IL-16-mimicking molecule to the host under conditions such that the expression of an inflammatory cytokine (e.g., IFN-xcex3, IL-1xcex2, and TNF-xcex1) in the region of the inflamed tissue is reduced. The host is in need of an anti-inflammatory treatment and can be a mammal (e.g., a human). The IL-16 polypeptide can be recombinant human IL-16, and the IL-16-mimicking molecule can be a recombinant HIV gp120 polypeptide. The method also can include administering, to the host, a polypeptide such as TGF-xcex21, IL-4 and/or IL-10.
In another embodiment, the invention features a method for treating an inflammatory disease (e.g., rheumatoid arthritis) in a host. The method includes providing nucleic acid to the host. The nucleic acid encodes an IL-16 polypeptide, and the host expresses the IL-16 polypeptide from the nucleic acid such that the expression of an inflammatory cytokine (e.g., IFN-xcex3, IL-1xcex2, and TNF-xcex1) is reduced in the host. The host can be a mammal (e.g., a human). The IL-16 polypeptide can be human IL-16. The method also can include providing a second nucleic acid to the host. The second nucleic acid encodes an immunosuppressive cytokine (e.g., TGF-xcex21, IL-4, or IL-10).
Another embodiment of the invention features a method for treating an inflammatory disease (e.g., rheumatoid arthritis) in a host. The method includes administering, to the host, cells that reduce the expression of an inflammatory cytokine (e.g., IFN-xcex3, IL-1xcex2, and TNF-xcex1). The host can be a mammal (e.g., a human). The cells can be, for example, synovial tissue-derived CD8+ T cells, cells that express IL-16 and/or TGF-xcex1, and/or cells containing exogenous nucleic acid encoding an IL-16 polypeptide. The IL-16 can be human IL-16. The cells can contain exogenous nucleic acid that encodes a polypeptide such as TGF-xcex21, IL-4, and/or IL-10. In addition, the cells can have specificity for a synovial antigen, and can accumulate within synovial tissue.
In another aspect, the invention features a pharmaceutical composition for treating an inflammatory disease (e.g., rheumatoid arthritis) in a host. The composition contains an IL-16 polypeptide (e.g., recombinant human IL-16) or an IL-16-mimicking molecule (e.g., a recombinant HIV gp120 polypeptide) and an immunosuppressive cytokine (e.g., TGF-xcex21, IL-4, and IL-10). The administration of the composition to the host reduces the expression of an inflammatory cytokine (e.g., IFN-xcex3, IL-1xcex2, and TNF-xcex1) in the host. The host can be a mammal (e.g., a human).
Another aspect of the invention features a non-human animal containing human synovial tissue. The non-human animal can be a murine animal. In addition, the non-human animal can be immunocompromised. For example, the immunocompromised non-human animal can be a SCID mouse or a recombination-activating gene-deficient animal. At least a portion of the human synovial tissue can be located under the skin and/or in the back region of the non-human animal. The human synovial tissue can be inflamed human synovial tissue. The inflamed human synovial tissue can be in a diffuse and/or follicular state of inflammation within the animal. The human synovial tissue can be diffusely vascularized human synovial tissue within the animal. The non-human animal can be a NOD/LtSz-Prkdcscid/J mouse having human synovial tissue derived from a rheumatoid arthritis patient.
Another aspect of the invention features a method for identifying a treatment reagent that reduces inflammation. The method includes administering a test reagent to a non-human animal having human synovial tissue, at least a portion of the human synovial tissue being inflamed, and determining if the administration of the test reagent reduces the inflammation. A reduction in inflammation indicates that the test reagent is a treatment reagent. The reduction in inflammation can be determined by measuring IFN-xcex3 production by the human synovial tissue.
Another aspect of the invention features an article of manufacture containing packaging material and an IL-16 polypeptide or IL-16-mimicking molecule. The packaging material contains a label or package insert indicating that the IL-16 polypeptide or IL-16-mimicking molecule can be administered to a host for the purpose of treating an inflammatory disease.
In another embodiment, the invention features an article of manufacture containing packaging material and nucleic acid encoding an IL-16 polypeptide. The packaging material contains a label or package insert indicating that the nucleic acid can be administered to a host for the purpose of treating an inflammatory disease.
Another embodiment of the invention features an article of manufacture containing packaging material and cells that reduce the expression of an inflammatory cytokine. The packaging material contains a label or package insert indicating that the cells can be administered to a host for the purpose of treating an inflammatory disease.
Another aspect of the invention features the use of an IL-16 polypeptide or an IL-16-mimicking molecule in the manufacture of a medicament for treating an inflammatory disease in a host in need of an anti-inflammatory treatment. The host has inflamed tissue, and administering a pharmaceutically effective amount of the medicament to the host reduces the expression of an inflammatory cytokine in the region of the inflamed tissue.
In another embodiment, the invention features the use of a nucleic acid in the manufacture of a medicament for treating an inflammatory disease in a host in need of an anti-inflammatory treatment. The nucleic acid encodes an IL-16 polypeptide. The host has inflamed tissue, and administering the medicament to the host reduces the expression of an inflammatory cytokine in the region of the inflamed tissue.
Another embodiment of the invention features the use of cells in the manufacture of a medicament for treating an inflammatory disease in a host in need of an anti-inflammatory treatment. The host has inflamed tissue, and administering the medicament to the host reduces the expression of an inflammatory cytokine in the region of the inflamed tissue.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.